576P Genome instability index used for the optimization of molecular classification of endometrial carcinoma

Abstract

The molecular classification of endometrial carcinoma (EC) has divided patients into four distinct prognostic subtypes based on the genomic abnormalities. However, in clinical application, the genomic copy number index lacks a simple and accurate detection method, and the method of using p53 immunohistochemistry or TP53 mutation as a surrogate for copy number status needs to be optimized. Here, we explored the application of genome instability (GI) index in molecular classification of EC. We assessed a retrospective cohort of EC from Beijing Cancer Hospital between 2011 and 2020. Genomic profiling of tumor tissues from EC patients was sequenced by OncoScreen Plus Panel of 520 cancer-related genes, and tumor immune microenvironment was evaluated using multiplex immunofluorescence staining. GI index was calculated as the sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. 143 patients were enrolled in this study, with the median follow-up time of 38.77 months. Molecular analysis firstly identified four different prognostic subgroups: POLE mutations (mut), MSI-H, TP53 wildtype, and TP53 mut. We also divided patients into two groups based on GI index: GI-high and GI-low, and patients with GI-high were found in three subgroups except for POLE mut. Further analysis showed that GI status had a more important effect on prognosis than TP53 mutation. Therefore, we proposed a three-group molecular classification based on POLE mutation and GI index: POLE mut (n=9, 6.5%), GI-low (n=116, 82.9%), and GI-high (n=15, 10.7%). Patients with GI-high had much poorer survival than those with GI-low [disease-free survival: hazard ratio (HR), 17.87, 95% CI, 6.67-50.00, P < 0.001; overall survival: HR, 16.75, 95% CI, 4.76-50.00, P < 0.001]. The application in TCGA-UCEC cohort containing 481 EC patients confirmed that this new method worked well for risk stratification of EC. Further analysis showed that patients in GI-high group had higher tumor grade, aneuploidy and lower T cell infiltrations. The one-stop method of GI index combined with POLE mutation offers more accurate and stable disease risk stratification and demonstrates the potential for guiding therapy for EC patients.